Synthesis and regioselective transformations of ethoxy-substituted 5-(perfluoroalkyl)pyrimidines

The reaction of 5-bromo-2,4-diethoxypyrimidine or 5-bromo-2-ethoxypyrimidine with a perfluoroalkyl iodide in the presence of Cu-bronze followed by acid hydrolysis of the resultant 5-perfluoroalkyl derivative furnishes the respective 5-perfluoroalkyluracil and 5-perfluoroalkylpyrimidin-2(1 H )one. The treatment of the perfluoroalkyluracil with NaOH or sodium alkoxide gives the respective 5-(perfluoroacyl)- or 5-(1,1-dialkoxyperfluoroalkyl)- substituted uracil. 5-(Perfluoroalkyl)pyrimidine-2(1 H )one is inert under these conditions.


Introduction
2][3][4] Most previous synthetic work has focused on the preparation of 5-(trifluoromethyl)uracil and its nucleosides, and reports on the synthesis of higher perfluoroalkyl derivatives are scarce.The reported synthetic routes to such compounds are inefficient, require the use of specialized equipment and starting materials that are difficult to obtain, and/or utilize toxic reagents or solvents.These are perfluoroalkylation of uracil and uridine by the reaction of their bis(trimethylsilyl) derivatives with bis(perfluoroalkanoyl) peroxides, 5 photochemically induced coupling by the reaction of uracil, its nucleosides or their expensive 5-iodo derivatives with toxic bis(perfluoroalkyl)mercury, 6 the electrochemically induced coupling, 7,8 and the highly inefficient reaction of uracil, its nucleosides or 5-iodouracil with a perfluoroalkyl iodide in the presence of copper bronze. 9,10The quite efficient reaction of 5-iodouracil nucleosides with trifluoromethylcopper requires an elaborate purification of the copper reagent but, in principle, could be extended to the preparation of higher perfluoroalkyl analogs. 11Unfortunately, this synthesis is not acceptable because the reaction, as reported, must be conducted in hexamethylphosphoramide which is a highly potent carcinogen.
Since 5-(perfluoroalkyl)uracils can be efficiently transformed into nucleosides, 3,4 our work has been focused on finding a facile synthesis of the former compounds, 12 as described in this paper.We also report efficient chemical modifications of 5-(perfluoroalkyl)uracils that involve regioselectively the benzylic-type difluoromethylene moiety of the perfluoroalkyl substituent.

Results and Discussion
In contrast to the inefficient coupling reaction of a 5-halouracil with a perfluoroalkyl iodide, as mentioned above, 9,10 the treatment of 5-bromo-2,4-diethoxypyrimidine (1) with perfluorobutyl iodide or perfluorohexyl iodide in the presence of activated copper bronze 9 in DMSO gave the respective 5-(perfluoroalkyl)pyrimidines 2a,b in high yields (Scheme 1).Acid-mediated hydrolysis of 2 furnished 5-(perfluoroalkyl)uracils 3, also in high yields.Compounds 3a,b are stable under acidic conditions but undergo an efficient hydrolysis by the reaction with hydroxide ion in aqueous solution to give the respective 5-(perfluoroacyl)uracils 6a,b.
4][15][16] A related mechanistic pathway has also been suggested for inhibition of thymidylate syntheses by 5-(trifluoromethyl)uracil which is used as an antitumor drug. 17Although perfluoroalkyl ketones, including 6, resist the formation of sp 2 -type condensation products such as hydrazones, they readily undergo an addition reaction with a number of nucleophiles to form stable sp 3 -type adducts. 18A greatly simplified synthetic route to acetals 7-9 by the reaction of 5-(perfluoroalkyl)pyrimidines 3 with alkoxide ions is given in Scheme 2. Interesting features in the 1 H NMR spectra of these acetals are a broadened signal for Omethylene protons of the ethoxy derivatives 7 and a well-defined single AB absorption pattern for the O-methylene protons of the benzyloxy groups of 8.As shown by decoupling experiments, these unusual absorption patterns are not due to a proton-fluorine coupling and, therefore, they must be a result of restricted rotation of the alkoxy groups around the central carbon atom of the acetal.In particular, the 1 H NMR spectra of 8 are consistent with the presence of a symmetric equilibrium conformation in which the pyrimidine plane bisects the acetal functionality.Due to symmetry, the two methylene moieties are equivalent but their geminal protons are not, thereby giving rise to a single AB system in the 1 H NMR spectrum, as observed.An interesting feature in the 1 H NMR spectrum of acetal 9 is a long-range coupling between C6-H of the uracil and two fluorine atoms of the perfluoroalkyl chain.This coupling gives rise to a doublet of doublets for C6-H at δ 7.56.An extension of this work on the successful synthesis of 2-ethoxy-5-(perfluoroalkyl)pyrimidines 11a,b, starting with 5-bromo-2-ethoxypyrimidine (10) and using a similar methodology, is given in Scheme 3.These products were efficiently hydrolyzed to give the expected 5-(perfluoroalkyl)pyrimidine-2(1H)ones 12a,b.In contrast to the facile transformations of their uracil analogs 3, as discussed above, compounds 12 are inert in the presence of base, even under forced conditions of an elevated temperature.For example, pyrimidinone 12a was recovered in a virtually quantitative yield after its solution in aqueous sodium hydroxide had been heated in a pressure vessel to 120 °C for 4 h.

Experimental Section
General Procedures.Melting points (Pyrex capillary) are not corrected. 1H NMR (400 MHz) and 19 F NMR (282 MHz) spectra were recorded in CDCl 3 at 25 °C or DMSO-d 6 at 30 °C with TMS and C 6 F 6 as the respective internal standards.Crude mixtures were analyzed, and EI mass spectra of pure components were obtained on a GC-MS instrument equipped with an on-column injector, a poly(dimethylsiloxane)-coated capillary column, and a mass selective detector operating at 70 eV.

Acetals 7a,b
A solution of 3 (1 mmol) in absolute EtOH (4 mL) was added under a nitrogen atmosphere to a solution of sodium ethoxide prepared from sodium (115 mg, 5 mmol) and absolute EtOH (5 mL).The mixture was heated under reflux for 8 h and then concentrated.Water (6 mL) was added to the residue and the solution was neutralized with Dowex cation exchange resin or hydrochloric acid (1 M) and concentrated.The product was crystallized from EtOH.

Acetals 8a,b
Sodium benzyloxide prepared from sodium hydride (120 mg, 5 mmol) and benzyl alcohol (5 mL) was allowed to react with 3 (1 mmol) in benzyl alcohol (5 mL) and the mixture was worked up as described above.The product was crystallized from ether.